CRCNS: Network Mechanisms Underlying Episodic Memory

CRCNS：情景记忆背后的网络机制

• 批准号: 8725234
• 负责人: JOHN E LISMAN
• 金额: $ 25.98万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725234
• 关键词: Brain; Cells; Code; Data Analyses; Data Set; Disadvantaged; Episodic memory; Ethics; Event; Fire - disasters; Goals; Hippocampus (Brain); Incidence; Knowledge; Laboratories; Maps; Memory; Methods; Minor; National Institute of Mental Health; Neurosciences; Pattern; Phase; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Process; Rattus; Sensory; Structure; Students; Testing; Underrepresented Minority; Work; aging population; dentate gyrus; experience; hippocampal subregions; insight; lectures; neural circuit; optogenetics; programs; relating to nervous system; research study; skills; therapeutic target

DESCRIPTION (provided by applicant): Intellectual Merit: Although considerable progress has been made in understanding how episodic memory is stored in the brain, fundamental questions remain. We will use a combination of experimental and computational approaches to study two major questions. Aim 1: Network mechanisms of sequence recall in the hippocampus: Our ability to recall a sequence of events is a core component of episodic memory. The hippocampus is necessary for episodic memory, and electrophysiological recordings from this structure have begun to reveal some of the processes involved. After a rat experiences a spatial path, it recalls sequences of places along that path during brief events called sharp waves. Recent experiments show that these waves are necessary for memory consolidation. Sharp waves are generated intrahippocampally, but the specific hippocampal subregions that produce them are not known. According to one hypothesis, CA3 alone generates the sharp wave. Another hypothesis (the ping-pong hypothesis) posits that sharp waves are generated by the combined action of the dentate gyrus (DG) and CA3.This hypothesis has its origins in the work of Sompolinsky and Kleinfeld, who argued that each cycle in sequence recall requires two substeps: a) a chaining substep in which cells representing one item stimulate the cells representing the next item in the sequence and b) an autoassociative substep that corrects minor errors produced in each chaining step, thereby avoiding concatenation of error. Lisman proposed how this could be mapped onto hippocampal circuitry: CA3 cells that represent the nth item in the sequence excite the n+1 item in the DG (by the known backprojections); then, the n+1 item in DG is sent to CA3 for error correction (pattern completion). This, in turn, initiates te next cycle. To distinguish between the ping-pong and CA3-alone hypotheses, J. Leutgeb will record simultaneously from dentate and CA3. She will determine whether both dentate and CA3 cells fire during sharp waves and whether they fire at a different phase of gamma oscillations, as would be expected from a ping-pong process. To test whether accurate sequence recall in CA3 requires the dentate, Leutgeb will use optogenetic methods. If the dentate is required, accurate sequence recall should be disrupted by artificially inducing activity in the dentate or by blocking activity in the dentate. The data analysis will be done in the Lisman laboratory. Aim 2: Neural coding in the hippocampus: Two key experiments have provided insight into how spatial and sensory information are encoded in the hippocampus. O'Keefe showed that different spatial positions in a sequence are represented in different phases of a theta cycle. The Moser lab demonstrated that sensory information is encoded by "rate remapping": sensory information associated with a place is encoded by a change in the firing RATE of the place cells that encode that position. It is unclear whether these major ideas are compatible: the increased number of spikes during rate remapping might smear theta phase and thereby compromise phase coding. To determine whether this is the case, Lisman will analyze an existing data set and a new data set to be obtained by Leutgeb. Our working hypothesis is that rate remapping increases the number of spikes in a brief burst; since the spikes in a burst have nearly the same theta phase, phase coding would not be significantly degraded. Broader Impact: Understanding memory is a major goal of neuroscience because of the increasing incidence of memory problems in an aging population. The proposed experiment will identify a key component of the neural circuitry that underlies episodic memory. This may enable more targeted therapeutic strategies. A second contribution will be a MATLAB tutorial for the Summer Program in Neuroscience, Ethics and Survival (SPINES). This is an NIMH-sponsored course aimed at helping grad students and postdocs from under-represented minority and disadvantaged groups to develop knowledge and skills. Lisman and Leutgeb will lecture on major advances in episodic memory and describe how computation is important in this endeavor. This will be followed by a one-month tutorial on the computational platform MATLAB.

描述（由申请人提供）：智力优点：尽管在了解情景记忆如何存储在大脑中方面取得了相当大的进展，但基本问题仍然存在。我们将结合实验和计算方法来研究两个主要问题。目的1：海马序列回忆的网络机制：我们回忆事件序列的能力是情景记忆的核心组成部分。海马体是情景记忆所必需的，从这个结构的电生理记录已经开始揭示一些涉及的过程。当老鼠经历了一条空间路径后，它会在被称为“锐波”的短暂事件中回忆起沿着这条路径沿着的一系列地点。最近的实验表明，这些波是必要的记忆巩固。尖波在海马内产生，但产生尖波的特定海马亚区尚不清楚。根据一种假设，CA 3单独产生尖波。另一个假说乒乓假说（ping-pong hypothesis）认为，尖波是由齿状回（dentate gyrus，DG）和CA 3共同作用产生的。这一假说起源于Sompolinsky和克莱菲尔德的工作，他们认为序列回忆中的每个循环都需要两个子步骤：a）链接子步骤，其中表示一个项目的单元激励表示序列中下一个项目的单元，以及B）自动关联子步骤，其校正在每个链接步骤中产生的小错误，从而避免错误的级联。Lisman提出了如何将其映射到海马电路上：代表序列中第n个项目的CA 3细胞（通过已知的反投影）激发DG中的n+1个项目;然后，DG中的n+1个项目被发送到CA 3进行错误校正（模式完成）。这反过来又启动了下一个周期。为了区分乒乓假说和CA 3单独假说，J. Leutgeb将同时记录齿状回和CA 3。她将确定齿状核和CA 3细胞是否在尖波期间发射，以及它们是否在伽马振荡的不同阶段发射，就像乒乓过程所预期的那样。为了测试CA 3中准确的序列回忆是否需要齿状，Leutgeb将使用光遗传学方法。如果需要齿状回，则应通过人工诱导齿状回的活动或 阻止了牙齿的活动。数据分析将在Lisman实验室进行。目标二：海马体中的神经编码：两个关键的实验提供了对空间和感觉信息如何在海马体中编码的见解。奥基夫表明，不同的空间位置在一个序列中表示在不同阶段的θ循环。Moser实验室证明，感觉信息是通过“速率重映射”编码的：与位置相关的感觉信息是通过编码该位置的位置细胞的发射速率的变化来编码的。目前还不清楚这些主要思想是否兼容：在速率重新映射期间增加的尖峰数量可能会涂抹θ相位，从而损害相位编码。为了确定是否是这种情况，Lisman将分析现有的数据集和Leutgeb获得的新数据集。我们的工作假设是，速率重新映射增加了短暂突发中的尖峰数量;由于突发中的尖峰具有几乎相同的θ相位，因此相位编码不会显著降低。 更广泛的影响：了解记忆是神经科学的一个主要目标，因为在老龄化人口中记忆问题的发生率越来越高。拟议的实验将确定一个关键组成部分的神经回路的基础情节记忆。这可以实现更有针对性的治疗策略。第二个贡献将是神经科学，伦理学和生存（SPINES）暑期课程的MATLAB教程。这是一个NIMH赞助的课程，旨在帮助来自代表性不足的少数民族和弱势群体的格拉德生和博士后发展知识和技能。Lisman和Leutgeb将讲述情景记忆的主要进展，并描述计算在这奋进的重要性。随后将在计算平台MATLAB上进行为期一个月的教程。